Introduction

Individuals with the Dutch founder CDKN2A/p16-Leiden pathogenic variant (PV) have an increased lifetime risk of melanoma (70%) and pancreatic cancer (20%). Consequently, skin surveillance is offered from the age of 12 to those with a confirmed or suspected PV, while pancreatic cancer surveillance is exclusively offered to confirmed carriers from the age of 40. It is unknown whether the CDKN2A PV impacts quality of life (QoL). Therefore, we aimed to assess QoL and psychological distress in individuals from affected families.

Aims & Methods

This cross-sectional study included confirmed carriers and those with a 50% risk of the CDKN2A PV (at-risk carriers) undergoing cancer surveillance. Individuals ≥18 years were identified from the skin and pancreatic cancer surveillance programs at the Leiden University Medical Center and invited for a one-time, validated self-report questionnaire, including the 12-Item Short Form Health Survey (SF-12), Hospital Anxiety and Depression Scale (HADS), and Cancer Worry Scale (CWS).

Results

A total of 537 individuals were screened for eligibility, of whom 59/249 (24%) individuals under skin surveillance (skin surveillance group) and 188/288 (65%) individuals under combined pancreatic cancer and skin surveillance (pancreatic cancer surveillance group) responded. In both surveillance groups, health-related QoL and general distress levels were within the general population norms (Table 1). However, more than 40% of all study participants reported melanoma-related distress. Pancreatic cancer-related distress was experienced by 45% of the pancreatic surveillance group. Determinants of cancer-related distress were a first-degree relative with melanoma or pancreatic cancer, increased cancer risk perception, and poor general health perception. Over 80% of the participants felt that the benefits of cancer surveillance outweigh the disadvantages.

Table 1. Descriptive statistics and summary of group comparisons for psychological variables

Scale	Scale range / threshold	Skin surveillance group (N = 59)	Pancreatic surveillance group (N = 188)	General population
		Mean (±SD) % > threshold	Mean (±SD) % > threshold	Mean (±SD) % > threshold
Health-related QoL
SF-12 PCS	Range 0-100	54.7 (6.6)**	50.4 (8.1)**	51.7 †/ 48.1‡
SF-12 MCS	Range 0-100	46.9 (10.1)	51.4 (8.8)	48.0 †/ 51.0 ‡
General and cancer-related distress
HADS - anxiety	Range 0-21 Abnormal threshold ≥ 11	4.7 (3.7) 6 (10%)	4.0 (3.6)** 11 (6%)	5.1 (3.6) § -
HADS - depression	Range 0-21 Abnormal threshold ≥ 11	2.8 (3.1) 2 (3%)	2.7 (2.8)* 3 (2%)	3.4 (3.3) § -
CWS - melanoma-related worries	Range 8-32 Abnormal threshold ≥ 14	12.7 (3.2) 26 (44%)	13.4 (3.9) 76 (40%)	-
CWS - pancreatic-related worries	Range 8-32 Abnormal threshold ≥ 14	11.4 (3.0) 10 (17%)	13.6 (3.9) 84 (45%)	-

**P<0.01. *P<0.05. SF-12, 12-item Short Form Health Survey; PCS, Physical Component Scale; MCS, Mental Component Scale; HADS, Hospital Anxiety and Depression Scale; cancer worries measured by the adapted Cancer Worry Scale (CWS). Scores of the SF-12 ranged from 0-100, with higher scores indicating better health. The HADS cut-off score was ≥ 11, indicating a clinically significant anxiety or depressive disorder. The CWS cut-off score was ≥ 14, indicating increased cancer-related distress. ^† age-matched QoL norm scores from Dutch general population with skin surveillance group. ^‡ age-matched QoL norm scores from Dutch general population with pancreatic surveillance group.^1§ HADS scores were compared with 199 individuals from the general Dutch population.²

Conclusion

In conclusion, confirmed and at-risk carriers of the CDKN2A PV experienced similar levels of QoL and general distress compared with the general population. However, cancer-related worry was substantial was substantial in this population. These findings can help identify individuals who may benefit from psychological support.

References

1. Netherlands S. Gezondheid en zorggebruik; persoonskenmerken. Accessed 05-01-2024.
2. Spinhoven PH, Ormel J, Sloekers PPA, Kempen GIJM, Speckens AEM, Hemert AMV. A validation study of the Hospital Anxiety and Depression Scale (HADS) in different groups of Dutch subjects. Psychological Medicine. 1997;27(2):363-370. doi:10.1017/S0033291796004382

Introduction

Upper gastrointestinal bleeding (UGIB) is still a significant cause of hospitalization with mortality as high as 10%. While there is a seasonal trend of UGIB, studies have also illustrated the potential association between air pollution exposure and UGIB. However, the relationship between exposure to ambient pollutants and emergency attendance for UGIB, particularly concerning seasonal changes, is still unknown.

Aims & Methods

We aimed to determine the association between high concentrations of ambient pollutants exposure and the risk of emergency attendance for UGIB during different seasons. This population-based time-series study was based on the Hong Kong population of 7.6 million. We retrieved detailed daily data on UGIB emergency attendance, ambient pollutants (PM_2.5, PM₁₀, CO, NO₂, SO₂, O₃), and meteorological data (including temperature, wind speed, and humidity) between January 1, 2016, and December 31, 2021. Emergency attendance was obtained from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority. Ambient pollutants and meteorological data were obtained from the Environmental Protection Department and the Hong Kong Observatory, respectively. The distributed lag non-linear model (DLNM) was adopted to investigate the association between ambient pollutants exposure and UGIB emergency attendance, considering the effects of lag days and confounding meteorological factors. To avoid issues caused by multi-collinearity, Spearman’s correlation coefficients of less than 0.7 were adopted to select the covariates. Subgroup analysis was performed after stratification by sex, age (<65 vs ≥65 years), or season (cold season: October to March; warm season: April to September). The risk ratio(RR) for ambient pollution exposure on UGIB emergency attendance was presented with 95% confidence interval (CI).

Results

Total number of UGIB emergency attendance during the six-year period was 22,109, of which 11,798 (53.4%) were male and 11533 (52.2%) were aged ≥65 years. PM₁₀(r=0.703), CO(r=0.709), and SO₂(r=0.717) were eliminated from the final regression model due to a close relationship with PM_2.5. Exposure to the high concentrations (90th percentile) of PM_2.5 and NO₂ significantly increased the UGIB emergency attendance risk, but not high concentration of O₃. High concentration of PM_2.5 exposure significantly increased the risk from lag days 5 to 7 (RR:1.08; 95% CI:1.01-1.15 to 1.09; 95%CI:1.02-1.16). For high concentrations of NO₂ exposure, single-day lag association shows a significantly higher risk from lag 3 to lag 5 (RR:1.13; 95%CI:1.01-1.27 to 1.12; 95%CI:1.02-1.22). For both high PM_2.5 and NO₂, stratified analysis showed that elderly, female and cold season are at higher risk of emergency attendance for UGIB.

Conclusion

High PM_2.5 and NO₂ exposure are associated with an increased risk of UGIB emergency attendance. The risk is further increased among elderly, female, or during cold seasons.

Introduction

The precise aetiology of inflammatory bowel disease (IBD) remains unclear with excess intestinal cell death implicated yet vastly understudied. Necroptosis, a recently described lytic cell death pathway, is emerging as a key player in intestinal inflammation in mouse models of colitis (1, 2), however clinical data are sparse. This non-apoptotic regulated cell death can be initiated by tumour necrosis factor (TNF) receptor activation and is executed by a core axis of proteins, including receptor-interacting protein kinase (RIPK) -1 and -3, and mixed lineage domain-like pseudokinase (MLKL) independent of caspases (3). The pathway is usually repressed by cellular inhibitor of apoptosis protein (cIAP) -1 and -2, and cellular FLICE-like inhibitory (cFLIP_L).
This project proposes the first study to comprehensively assess programmed cell death in intestinal tissue of adult patients with IBD using a novel toolbox of affinity reagents (4). By comparing this with non-inflamed control tissue, we have uncovered a new molecular defect in IBD: loss of essential cellular death brakes, even in tissue with apparent mucosal and histologic healing. This novel finding may underpin the vicious cycle of remission and disease relapse and poses a step towards molecular healing through restoration of these brakes.

Aims & Methods

Aims:

1. Assess cell death prevalence in IBD
2. Determine why cell death brakes disappear in intestinal IBD tissue, regardless of inflammatory status
3. Determine whether IBD phenotypes can be uniquely profiled according to cell death signals

Methods: Matched intestinal biopsies are retrieved endoscopically from patients without IBD (healthy controls) and those with IBD. Patients requiring endoscopy as part of standard of care are screened for eligibility: exclusion criteria comprise active malignancy, non-IBD inflammation, infection, use of non-steroidal anti-inflammatory drugs, and polyposis syndromes. Biopsies from participants with IBD are taken from macroscopically non-inflamed, margin and inflamed areas. Control specimen are taken from healthy-appearing bowel. Specimen are collected fresh for investigation of pertinent targets (Table 1). Clinical/endoscopy activity indices, biochemical markers (C-reactive protein, faecal calprotectin) and blinded histologic (Robarts Histopathology Index) scoring are correlated with laboratory data in a multi-parametric manner.

MEDIUM	TECHNIQUE	PURPOSE
Phosphate buffer system + protease + phosphatase inhibitors	Immunoblotting	Protein quantification of 26 cell death-related proteins
10% formalin	Immunohistochemistry	Visualisation of 12 cell death-related markers
Methanol + 5% acetic acid	Immunofluorescence	Optic microscopy of necroptosis hot-spots
RNA later	RNA sequencing	Shotgun transcriptomics of host microbiome, immune and inflammatory infiltrates
Dulbecco's Modified Eagle Medium: Nutrient Mixture F12 (DMEM F12) + Primocin	Organoid development	Gut organoid challenges to identify factors impacting cell death

Results

Intestinal biopsies from 28 healthy controls and 52 patients with IBD: 25 UC; 25 CD; and 2 pouchitis have been collected. Interim analysis demonstrates suppression of cell death inhibitory proteins- cIAP-1, -2 and cFLIP_L even in non-inflamed tissue in patients with IBD, unleashing apoptosis (hallmarked by a statistically significant increase in cleaved caspase-3) and/or necroptosis (hallmarked by statistically significant increases in phosphorylated RIPK-3) in nearby tissue.

Conclusion

For the first time, we demonstrate that cellular death brakes are removed in intestinal tissue in IBD, despite histologic remission. Our findings challenge current dogma that necroptosis occurs in the absence of apoptosis and that necroptosis is universally increased in all forms of IBD. Disinhibition of programmed cell death is likely intrinsic to the inflammatory sequence underlying disease recurrence and progression.

References

1. Günther C, Martini E, Wittkopf al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature. 2011 Sep 14;477(7364):335-9
2. Patankar JV, Müller TM, Kantham S et al. E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nature Cell Biology. 2021 Jul;23(7):796-807
3. Horne CR, Samson AL, Murphy JM. The web of death: the expanding complexity of necroptotic signaling. Trends in Cell Biology. 2023 Feb;33(2):162-174
4. Samson AL,Fitzgibbon C, Patel KM et al. A toolbox for imaging RIPK1, RIPK3, and MLKL in mouse and human cells. Cell Death & Differentiation. 2021 Jul;28(7):2126-2144

Disclosure

AHA is supported by scholarships from the University of Melbourne/Australian Commonwealth Government, Crohn's and Colitis Australia, Avant Foundation, and a grant from the Gastroenterological Society of Australia and Celltrion Healthcare. ALS has received funding from the National Health and Medical Research Council (Grant 2002965). JMM has received funding from the National Health and Medical Research Council (Grants 1172929, 9000719). ALS and JMM contribute to a project developing necroptosis inhibitors with Anaxis Pharma Pty.

Introduction

There is controversy about the management of low-risk pT1 CRCs resected in piecemeal, due to impossibility in assessing margins and potential suboptimal histological risk stratification in a fragmented and cauterized specimen.

Aims & Methods

Aims:To compare en bloc and piecemeal resected low-risk pT1CRC in terms of overall survival (OS) and metastasis free survival (MFS).
Materials and Methods: Low risk pT1 CRCs (no poor differentiation and no lymphovascular invasion) either piecemeal or en bloc resected were selected from two combined European multicenter cohorts (EpiT1 Consortium and Dutch pT1CRC study group). The exclusion criteria were primary surgical treatment, incomplete local resection, lack of information on type of resection , lack of follow-up of at least 2 years. The outcomes studied were metastasis free survival(MFS) and overal survival(OS). Cox regression analysis was performed adjusting for rectal location, size, and pedunculated morphology.

Results

Results: 3918/7043 patients with a pT1 CRC met the inclusion criteria: 822 (21%) resected in piecemeal and 3096 (79%) resected en bloc (Table 1). After local treatment, 46.6% in the piecemeal group received completion oncological surgery and 26.6% in the en bloc group. Adjusted 5-yrs MFS was lower for the piecemeal resected pT1 CRCs (94.6% (95%CI) vs. en bloc 97.4% (95%CI);p=0.001). Within the piecemeal resected pT1CRC group, the adjusted 5-yrs MFS did not differ between the group which underwent completion surgery versus the group who received only surveillance. (93.7%(95%CI) vs 96.3% (95%CI), p=0.08). Patients with a pT1 CRC resected in piecemeal followed by secondary surgery showed more endoluminal recurrence than en bloc resected pT1 CRCs followed by surveillance (10.8% VS 1.6%, p<0.00), higher proportion of distant metastasis (13/381 (3.4%) vs 14/730 (1.9%), p = 0.04) despite a similar 5-yrs MFS (96.3% vs 97.8%, p=0.08).

TABLE 1. Baseline characteristics of the patients (Multivariate analysis)

Variable	Piecemeal (N = 822)	En bloc (N = 3096 )	P
Age, median+SD	66.88 + 9.7	66.59 + 9.4	0.46
Female Sex, n (%)	317 (38.6)	1168 (37.7)	0.66
ASA Classification ,n (%) I-II III-IV	N=795 636 (80.0) 159 (20.0)	N=2971 2399 (80.7) 572 (19.3)	0.63
Polyp size, mm, DE	28.04+13.23	18.93+10.32	<0.001
Location, n (%) Rectum No rectum	N=818 284(34.7) 534 (65.3)	N=3079 816 (26.5) 2263(73.5)	<0.001
Morphology Not Pedunculated Pedunculated	N=789 516 (65.4%) 273 (34.6%)	N=3002 1263 (42.1%) 1739 (57.9)	<0.001
Treatment Surveillance Oncological surgery	N=822 441(53.6%) 381 (46.4%)	N=3096 2366 (76.4%) 730 (26.6%)	<0.001

Conclusion

Conclusions: Even after secondary surgery Piecemeal resected pT1 CRC have a worse outcome than en bloc resected pT1 CRCs with surveillance . This is probably due to suboptimal histological risk stratification in a fragmented and cauterized specimen.

Introduction

Previous observational studies reported a higher effectiveness of colonoscopy in preventing distal vs. proximal colorectal cancer (CRC) which we could not reproduce in a recently published observational study using target trial emulation (TTE). The design of the previous studies suffered from “time zero violation”, i.e. eligibility check, treatment assignment (screening vs. no screening) and start of follow-up were not synchronized.

Aims & Methods

We aimed to assess whether this “time zero violation” falsely induces a site-specific difference in the effect of colonoscopy. We used the same dataset underlying our recently published analysis (Braitmaier et al. 2022) based on German claims data (20% population coverage). We assessed the effect of screening colonoscopy in preventing distal and proximal CRC over 11 years of follow-up in 55–69-year-old persons at average CRC risk. Unlike in our recently published analysis, we used the design of previous observational studies with “time zero violation”. We compared the findings of both analyses.

Results

While in the recently published analysis using TTE, the relative risk (RR) of distal and proximal CRC in the screening colonoscopy vs. control group was similar (RR: 0.67 for distal, 0.70 for proximal), the analysis with “time zero violation” indicated a difference in site-specific performance. In this latter analysis, the RR was 0.41 for distal CRC and 0.66 for proximal CRC.

Conclusion

Our study demonstrates that “time zero violation” can substantially bias the results of observational studies. In our example, it falsely suggested an almost double preventive effect of colonoscopy in the distal vs. the proximal colon. The difference disappeared when the same data were analyzed using a TTE approach, which is known to avoid design-induced biases.

References

Braitmaier M, Schwarz S, Kollhorst B, Senore C, Didelez V, Haug U (2022) Screening colonoscopy similarly prevented distal and proximal colorectal cancer: a prospective study among 55-69-year-olds; Journal of Clinical Epidemiology; 149: 118-126

Introduction

The quality of colonoscopy is influenced by patient and operator factors. Studies investigating operator attentional fatigue on adenoma detection rate (ADR) have yielded conflicting results.

Aims & Methods

This study aims to compare ADR, polyp detection rate (PDR) and sessile serrated lesion detection rate (SSLDR) and complication rates between elective colonoscopies performed early and late in the list, across multiple operators (n>15), over 10 years, in a tertiary Brisbane (Australia) hospital.
A retrospective study was conducted on elective colonoscopies performed between 2012 and 2022 at The Prince Charles Hospital. ‘Early procedures’ are defined as procedures starting in the first hour of the first procedure starting and ‘late procedures’ are defined as procedures starting within the last hour of the last procedure starting. This pre-defined early and late procedures were used as surrogate markers for operator fatigue, accounting for a possible non-linear relationship between time and onset of fatigue, as well as the variation in number of colonoscopies performed every hour. Timing and the order of colonoscopy were used as alternative surrogates, in a secondary analysis.
Logistic regression was performed on all categorical outcome variables, and Poisson regression was modelled on continuous outcome variables, due to their non-linear distribution. Multivariate analysis included all potential confounding variables related to outcomes of interest. Statistical significance was defined as a P-value less than 0.05. Statistical analyses were performed using the SAS® statistical software (SAS Institute Inc, USA).
Exclusion included; surveillance for IBD and elective ESD.

Results

In total, 15 proceduralist (11 gastroenterologists, 4 surgeons) performed 39, 206 elective colonoscopies from 2012 to 2022. The baseline characteristics of patients, year and procedure sessions are similarly distributed between the early and late groups.
Multivariant analysis found significant associations between late procedures and lower adenoma detection rates, polyp detection rates and SSL detection rates. After adjusting for age, gender, proceduralist, year, morning or afternoon procedure, and bowel preparation quality, PDR, ADR and SDR remain 20-28% lower in late colonoscopies compared with early ones. We also found that age, gender, proceduralist, year and bowel preparation independently affected ADR in multivariant analysis. However, morning or afternoon ADRs did not significantly differ after adjusting for other variables. Proceduralist were found to be the only additional significant variable for SDR in multivariant analysis. There was no significant association between timing of procedures and major adverse events.

Conclusion

This is the largest single-centre study on operator fatigue and its effect on colonoscopy quality. Although the minimum standards for ADR was achieved, ‘late procedures’ have statistically significant lower ADR, PDR and SSLDR compared to ‘early procedures’. There was no difference in the complication rates between ‘early procedures’ and ‘late procedures’.
This study highlights the detrimental effect of fatigue in later procedures affecting the quality of colonoscopies and may be applicable in principal to other procedural based clinical work. Importantly, this may or perhaps will or is having an impact on patient safety, satisfaction, outcomes and clinical KPI’s for the operators and hospital administrators.

Disclosure

None